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Original Research: Chest Infections |

Risk of Mycobacterial Infections Associated With Rheumatoid Arthritis in Ontario, CanadaMycobacterial Infections and Rheumatoid Arthritis FREE TO VIEW

Sarah K. Brode, MD; Frances B. Jamieson, MD; Ryan Ng, MSc; Michael A. Campitelli, MPH; Jeffrey C. Kwong, MD; J. Michael Paterson, MSc; Ping Li, PhD; Alexandre Marchand-Austin, BSc; Claire Bombardier, MD; Theodore K. Marras, MD
Author and Funding Information

From the Joint Division of Respirology (Drs Brode and Marras), Department of Medicine and Toronto Western Family Health Team (Dr Kwong), University Health Network and Mount Sinai Hospital, Toronto; Westpark Healthcare Centre (Dr Brode), Toronto; Department of Medicine (Drs Brode and Marras), Department of Laboratory Medicine and Pathobiology (Dr Jamieson), Department of Family and Community Medicine (Dr Kwong), and Institute of Health Policy (Mr Paterson and Dr Bombardier), Management and Evaluation, University of Toronto, Toronto; Public Health Ontario (Drs Jamieson and Kwong and Mr Marchand-Austin), Toronto; Institute for Clinical Evaluative Sciences (Messrs Ng, Campitelli, and Paterson and Drs Kwong and Li), Toronto; Department of Family Medicine (Mr Paterson), McMaster University, Hamilton; and Toronto General Hospital Research Institute (Dr Bombardier), Toronto, ON, Canada.

CORRESPONDENCE TO: Theodore K. Marras, MD, Toronto Western Hospital, 7E 452, 399 Bathurst St, Toronto, ON, M5T 2S8, Canada; e-mail: ted.marras@uhn.ca


FOR EDITORIAL COMMENT SEE PAGE 529

Part of this article was presented in abstract form (Brode SK, Jamieson FB, Ng R, et al. Am J Respir Crit Care Med. 2013;187:A3793).

FUNDING/SUPPORT: The Grant-in-Aid Program of the Ontario Thoracic Society and Ontario Lung Association funded this research. This research was also supported by the Institute for Clinical Evaluative Sciences, a nonprofit research institute funded by the Ontario Ministry of Health and Long-Term Care.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(3):563-572. doi:10.1378/chest.13-2058
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OBJECTIVE:  Patients with rheumatoid arthritis (RA) are at increased risk of TB. Little is known about the risk of nontuberculous mycobacteria (NTM) disease in these patients. We sought to ascertain the rate of NTM infection and TB in all residents of Ontario, Canada, with and without RA.

METHODS:  In a cohort study, all Ontarians aged ≥ 15 years in January 2001 were followed until December 2010. Individuals with RA were identified using a validated algorithm to search hospitalization and physician billing claims. We linked Public Health Ontario Laboratory data to identify all cases of laboratory-confirmed TB and NTM disease. Analysis was performed using Cox proportional hazards regression.

RESULTS:  We identified 113,558 Ontarians with RA and 9,760,075 Ontarians without RA. Relative to the non-RA group, adjusted hazard ratios (HRs) and 95% CIs for TB (1.92, [1.50-2.47]) and NTM disease (2.07, [1.84-2.32]) demonstrated increased risks in the RA group. Among those with RA, per 100,000 person-years, NTM disease (HR, 41.6; 95% CI, 37.1-46.5) was more common than TB (HR, 8.5; 95% CI, 6.5-10.8). After full adjustment, people with RA who developed NTM disease were 1.81 times as likely to die than uninfected people with RA.

CONCLUSIONS:  Mycobacterial infections are more common in Ontarians with RA, with NTM disease more likely than TB. NTM disease is associated with an increased risk of death in patients with RA. Given the rising rates of NTM disease worldwide, determining whether this risk is due to the use of immunosuppressive medications vs RA itself is an important objective for future research.

Figures in this Article

TB is a leading cause of mortality worldwide and continues to be a problem in Canada, mainly due to the immigration of infected people. Generally well-standardized, treatment of TB typically spans 6 months, with success rates exceeding 95% and low rates of recurrence.1 Nontuberculous mycobacteria (NTM) are environmental organisms that can cause severe, predominantly pulmonary, infections without person-to-person transmission. NTM disease is increasingly common, with incidence and prevalence substantially exceeding TB in Ontario.2 NTM disease is most common in the elderly3 and causes important impairments in quality of life.4 Treatment of NTM typically spans 18 months, requires multiple drugs, and has overall success rates of only about 56% and high recurrence rates.5

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory arthritis associated with significant morbidity and mortality that currently affects approximately 300,000 Canadians.6 The introduction of anti-tumor necrosis factor (TNF) agents for the treatment of RA has raised concerns regarding the risk of TB in this patient population. Patients with RA have increased rates of TB compared with the general population, independent of anti-TNF therapy710; however, there are few data regarding NTM infection in RA. To clarify issues surrounding mycobacterial disease in patients with RA, we sought to determine the rates of NTM infection and TB in all residents of Ontario, Canada, with and without RA.

Study Population and Setting

We conducted a population-based cohort study using linked health administrative data and Public Health Ontario Laboratory data from Ontario. We included all people in Ontario’s Registered Persons Database aged ≥ 15 years on January 1, 2001, and followed them until the earliest of emigration, death, or December 31, 2010. Ontario residents have universal public health insurance under the Ontario Health Insurance Plan (OHIP), the single payer for medically necessary services. We excluded people who were ineligible for OHIP coverage (eg, immigrants during their initial 3 months of residence). We obtained ethics approval from the research ethics boards of the University of Toronto (26090) and University Health Network (11-1018-AE), both in Toronto, Canada.

Data Sources and Definitions

The Registered Persons Database, which contains demographic and vital status information about every Ontario resident with a valid health card, was used to identify and characterize our cohort. To identify individuals with RA and comorbidities, we used the Canadian Institute for Health Information Discharge Abstract Database, which contains diagnostic and procedural information recorded during admissions to acute care hospitals, and the OHIP Claims History Database, which contains physician billing claims for inpatient and outpatient services. We used a validated algorithm to identify individuals with RA (Fig 1).1117 Comorbidities, including diabetes mellitus, chronic kidney disease, HIV infection, asthma, COPD, and gastroesophageal reflux disease (GERD), were also identified with validated algorithms.1823 We looked back from cohort entry to April 1, 1991 (the earliest date available), to identify RA and comorbidities.

Figure Jump LinkFigure 1  Key study definitions. ICD = International Classification of Diseases; M. = Mycobacterium.Grahic Jump Location

Outcomes were identified by linking patient records from health administrative databases with the Public Health Ontario Laboratory database, which captures isolates from 100% of TB cases and approximately 95% of NTM cases in Ontario.2 Microbiologic methods are described in e-Appendix 1. Case definitions of TB and NTM are presented in Figure 1. Consistent with accepted guidelines, NTM infection was defined as either “isolation” or “disease.” Findings relating to NTM disease are presented in this article, while findings relating to NTM isolation are presented in e-Appendix 2. We also assessed the relative frequencies of individual NTM species associated with disease in patients with RA and those without RA by pulmonary vs nonpulmonary disease.

Statistical Analysis

Characteristics of Ontarians with and without RA were compared using one-way analysis of variance for continuous variables and χ2 tests for categorical variables. Incidence of TB and NTM (collectively referred to as mycobacterial syndromes) was expressed relative to follow-up time (person-years) among Ontarians with and without RA. For the non-RA group, follow-up time began on January 1, 2001, and was censored at death, RA diagnosis (date of first diagnosis code), or end of the study period, whichever came first. Follow-up time for patients with RA began on January 1, 2001 (for prevalent cases), or the date of the first diagnosis code for RA, and was censored at death or end of the study period, whichever came first. Thus, patients in the non-RA group who were subsequently diagnosed with RA contributed person-years to the non-RA group until the date of RA diagnosis and contributed person-years to the RA group after diagnosis. Follow-up was not censored at the time of diagnosis of a mycobacterial syndrome for incidence calculations, but was censored at diagnosis of a mycobacterial syndrome for determination of hazard ratios (HRs).

We attributed TB and NTM cases to RA if the patient was in the RA cohort before the occurrence of the mycobacterial syndrome. We looked back 3 years prior to the study period to find preexisting cases of mycobacterial syndromes. Due to the chronic nature of NTM lung disease, cases of incident NTM were excluded in any patient who previously had the same NTM species isolated during the look-back period. However, cases of TB were included in any given patient who previously had TB isolated, as long as the interval between positive TB culture results was at least 18 months.

Incidence was calculated as events per 100,000 person-years with Poisson 95% CIs. HRs comparing RA and non-RA groups were calculated using Cox proportional hazards regression. A time-dependent variable for the diagnosis of RA was used in the analysis to account for patients developing RA during follow-up. Adjustment was made for age, sex, income, rurality, and comorbidities known to increase the risk of TB and NTM; comorbidities were modeled in a time-varying fashion. Among patients with RA, mortality risk after mycobacterial disease was modeled using Cox proportional hazards regression with time-dependent covariates used to switch patients with RA from uninfected to infected with TB or NTM during follow-up. To control for RA disease severity in mortality analyses, we included extraarticular RA as a covariate.24 Analyses were performed using SAS, version 9.2 (SAS Institute Inc) and Stata, version 9.2 (StataCorp LP). All tests were two-tailed with the type 1 error (α) rate set at 5%.

We identified 59,017 individuals with RA as of January 1, 2001, and 54,541 individuals who developed RA during the study period, for a total 113,558 individuals with RA. There were 9,760,075 individuals who never developed RA. Ontarians with RA were more frequently female, older, more likely to have comorbidities (except HIV), and more likely to die during the study period than those in the non-RA group (Table 1).

Table Graphic Jump Location
TABLE 1  ] General Characteristics of Ontarians With and Without RAa

Data given as No. (%) unless otherwise indicated. GERD = gastroesophageal reflux disease; RA = rheumatoid arthritis.

a 

Ontarians aged ≥ 15 y as of 1/1/2001. People in the non-RA group never fulfilled RA criteria during the observation period, while people in the RA group fulfilled RA criteria at some time during the observation period.

In the RA group, we identified 64 cases of TB and 298 cases of NTM disease. In the non-RA group, we identified 3,154 cases of TB and 7,526 cases of NTM disease. Relative to the non-RA group, incidence rates of TB and NTM disease were statistically significantly higher in the RA group. Among those with RA, NTM disease was more common than TB, but adjusted HRs did not markedly differ, reflecting the greater frequency of NTM overall. Most cases of mycobacterial disease were pulmonary; lung infection accounted for 64% to 72% of TB cases and 88% to 92% of NTM disease cases. Although nonpulmonary NTM disease represented a minority of cases, the HR associated with RA for nonpulmonary NTM disease was double that for pulmonary NTM disease (Table 2). Including Mycobacterium gordonae in the analyses did not significantly change the results (data not shown).

Table Graphic Jump Location
TABLE 2  ] Mycobacterial Syndromes: Number of Cases, Incidence (per 100,000 Person-Y), and HRsa

HR = hazard ratio; NTM = nontuberculous mycobacteria. See Table 1 legend for expansion of other abbreviations.

a 

HR for mycobacterial syndrome in Ontarians with RA vs those without RA.

b 

Fully adjusted HR adjusted for age, sex, income, rurality, and comorbidities for TB: HIV, diabetes, and chronic kidney disease; and for NTM: HIV, COPD, asthma, and GERD.

c 

NTM disease: Pulmonary: isolation of the same NTM species from two or more sputum samples, or one or more bronchoscopy samples, excluding Mycobacterium gordonae; nonpulmonary: any positive culture from a normally sterile body site, excluding M gordonae (pleural isolates classified as nonpulmonary).

Within the RA group, those who developed TB were more frequently older, urban dwellers, and more likely to have diabetes, chronic kidney disease, and GERD than uninfected people. Those who developed NTM disease were more frequently older and urban dwellers and more likely to have chronic kidney disease, asthma, COPD, and GERD than uninfected people with RA. After adjustment for age, sex, comorbidities, and presence of extraarticular RA, people with RA who developed NTM disease were 1.81 times as likely to die by the end of follow-up as uninfected people with RA (Table 3).25 The species distribution of NTM causing pulmonary and nonpulmonary NTM disease are presented in Figure 2.

Table Graphic Jump Location
TABLE 3  ] Characteristics of TB and NTM Disease Cases Compared With Noncases Among People With RA

Data given as No. (%) unless otherwise indicated. According to privacy regulations, values representing fewer than six people are reported as ≤ 5. N/A = not applicable. See Table 1 and 2 legends for expansion of abbreviations.

a 

P value for comparison between TB cases and uninfected people.

b 

P value for comparison between NTM disease cases and uninfected people.

c 

Rural index for Ontario group is a measure of rurality designed for Ontario.24

d 

Fully adjusted HR adjusted for age, sex, income, rurality, presence of extraarticular RA, and comorbidities for TB: HIV, diabetes, and chronic kidney disease; and for NTM: HIV, COPD, asthma, and GERD.

Figure Jump LinkFigure 2  Distribution of NTM species causing disease in RA and non-RA groups. A, RA group, pulmonary NTM; B, non-RA group, pulmonary NTM; C, RA group, nonpulmonary NTM; D, non-RA group, nonpulmonary NTM.Grahic Jump Location

In this population-based study of almost 10 million people, including > 113,000 with RA, we found that the presence of RA was associated with an approximately twofold higher adjusted incidence of TB and NTM. Importantly, among people with RA, the incidence of NTM disease was approximately fivefold higher than that of TB. Also, NTM disease was associated with an increased risk of death in people with RA.

The association between RA and TB has been described previously. Most prior studies demonstrated a twofold to 10-fold increased risk of TB in patients with RA,710,26,27 whereas one study did not.28 This latter study identified TB using patient surveys, possibly underestimating the rate of TB owing to the underparticipation of foreign-born and minority populations. The association between RA and NTM infection is understudied. Winthrop et al27 studied the risk of TB and NTM disease associated with the use of anti-TNF medications in a single health maintenance organization (HMO). They found that the rate of NTM disease was higher in users of anti-TNF compared with the unexposed RA population, and the rate of NTM disease was higher than that of TB.27 They also found that the rate of NTM disease in patients with RA who were not exposed to anti-TNF agents was higher than in the general population. The rate of NTM disease was 19.2 per 100,000 person-years in unexposed patients with RA, compared with 4.1 per 100,000 person-years in the general HMO population and 11.8 per 100,000 person-years among the general HMO population aged ≥ 50 years. Similarly, we found the incidence of NTM disease to be substantially greater than that of TB in those with RA, which was not surprising given that our study was conducted in an area of low TB prevalence, where the incidence of NTM lung disease exceeds that of TB.3 Nonetheless, it highlights an important, potentially underappreciated risk in patients with RA. The twofold greater mortality risk associated with NTM disease further substantiates the importance of these infections. Additionally, NTM disease rates are increasing. In Ontario, pulmonary NTM isolation more than doubled during the period between 1997 and 2007,2 and pulmonary NTM disease increased 1.5-fold during the period between 2003 and 2008.3 Investigations from the United States have found similar rates and temporal increases in NTM lung disease.15,17,29 Therefore, NTM disease will be an increasingly important problem for patients with RA.

Adjusting for age and sex decreased the magnitude of the association between NTM disease and RA, although a statistically significant relationship persisted. RA and NTM disease are both more common in older age groups.3,30 The prevalence of pulmonary Mycobacterium avium complex disease in Ontario in 2008 was 18.6 per 100,000 in people aged ≥ 50 years, 27.5 per 100,000 in people aged ≥ 60 years, and 39 per 100,000 in people aged ≥ 70 years.3 Regarding sex, RA is two to three times more common in the female population,30 and pulmonary NTM disease also has a female predominance.16 The overlapping demographic profiles between RA and NTM disease in general explain some of the observed association between these entities, but the adjusted association indicates that RA itself is an important risk factor for NTM disease.

Several additional factors may contribute to the association between RA and NTM disease. Patients with RA are at risk for acquiring a number of chronic lung conditions, including bronchiectasis, bronchiolitis, and interstitial lung disease,31 and chronic lung disease is a known risk factor for pulmonary NTM disease.16,17,32,33 However, given the relative rarity of noninfective chronic lung disease secondary to RA, it is uncertain whether this risk factor could explain the high rates of NTM disease that we observed. Perhaps more importantly, the large HR for nonpulmonary NTM disease that we observed in our RA group (5.02) implies that some other mechanism must be present to preferentially predispose these patients to nonpulmonary NTM disease.

Another potential explanation for the association between RA and NTM disease is the use of immunosuppressive medications. Corticosteroids and disease-modifying antirheumatic drugs (both biologic and nonbiologic) increase the risk of TB in patients with RA.7,28,3439 Additionally, such medications, particularly anti-TNF agents, result in higher proportions of extrapulmonary and disseminated TB than those typically observed in immunocompetent individuals.35,40 Immunosuppressive medications may similarly put patients with RA at risk for NTM disease, including a particular disposition for extrapulmonary disease.

A final potential explanation for the association between RA and mycobacterial disease is that the RA itself may be associated with a state of immune dysregulation that increases susceptibility to mycobacterial infections. People with RA have immunologic abnormalities of T cells, impairing their ability to respond to novel antigenic stimuli,41 and disease activity is associated with an increased risk of infection in patients with RA on stable immunosuppressive therapy.42 This increased risk of infection may be related to altered levels of adipokines, based on an observed significant inverse correlation between active inflammation and leptin concentrations in patients with RA, such that patients with high levels of inflammation had low leptin levels.43 Leptin plays a role in both innate and adaptive immunity through its effects on lymphocytes (inducing lymphopoeisis, stimulating T-cell differentiation into the T helper cell type 1 phenotype, increasing T-cell survival)44 as well as macrophage activation and stimulation of cytokine production.45 Therefore, low leptin levels may predispose patients with RA to infections. Interestingly, adipokines are abnormally regulated in patients with pulmonary NTM,46 possibly suggesting a specific link between RA and NTM infections.

Our study has several important limitations. First, without population-based data on drug exposure, we were unable to determine the extent to which antirheumatic drugs influence mycobacterial infection risk in RA. Other exposures may also be relevant; for example, smoking is a risk factor for TB.47 However smoking is generally impossible to study in population-level databases, and its relevance to NTM is unknown (aside from the development of COPD, which we have addressed). Second, data limitations precluded assessment of differential monitoring and testing for infection in patients with RA compared with the general population; differential ascertainment bias may partly explain why patients with RA have higher detected rates of NTM infections. Although our findings are consistent with prior work, it should be noted that this issue was not previously discussed or investigated.27 Third, we identified RA using an administrative data algorithm. Although it was reported to have extremely high specificity (100%) and a respectable positive predictive value (76%) in a primary-care sample,12 its moderate sensitivity (78%) suggests that some unknown number of true RA cases would have been misclassified as non-RA. Given the low prevalence of RA and rarity of TB and NTM coinfection, however, we believe the misclassification is likely to have limited impact on our results and, regardless, would serve to bias any observed differences toward the null. Similarly, any inaccuracy in our estimation of the RA diagnosis date is likely to have biased comparisons toward the null. Finally, we defined TB and NTM disease wholly based on microbiology. This underestimates rates of TB by ignoring clinically diagnosed, culture-negative cases, which make up nearly 20% of TB cases in Canada.48 With respect to NTM disease, lacking clinical data may have led us to mislabel some patients with NTM colonization as having disease, resulting in an overestimation of disease rates. However, given the large number of mycobacterial infections that we observed, confirming all cases clinically would not have been feasible. Additionally, microbiologically based outcome definitions have been shown to be highly sensitive and accurate for both TB and NTM.49

In summary, patients with RA are at increased risk for mycobacterial infections, and these infections are associated with an increased risk for death. NTM disease is more likely than TB in Ontarians with RA, and RA may preferentially predispose patients to nonpulmonary NTM disease. Lack of data on medication use limits inferences regarding the cause of the increased risk. Given the rising rates of NTM disease, determining whether this risk is due to the use of immunosuppressive medications, rather than to RA itself, is an important objective for future research.

Author contributions: T. K. M. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. S. K. B. served as principal author. S. K. B. and T. K. M. contributed to the concept and design of the study, drafting and revision of the manuscript, and approval of the final version of the manuscript; F. B. J., J. C. K., J. M. P., and C. B. contributed to the concept and design of the study, revision of the manuscript, and approval of the final version of the manuscript; R. N. contributed to the concept and design of the study, data acquisition and analysis, revision of the manuscript, and approval of the final version of the manuscript; M. A. C. and P. L. contributed to the concept and design of the study, data analysis, revision of the manuscript, and approval of the final version of the manuscript; and A. M.-A. contributed to the concept and design of the study, data acquisition, revision of the manuscript, and approval of the final version of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Bombardier declares that she has acted as a consultant for Abbott Laboratories, AstraZeneca PLC, Bristol-Myers Squibb Co, UCB Canada Inc, and Amgen Inc; has been a member of the advisory boards of Hospira Inc, Janssen Global Services LLC, Pfizer Inc, and Takeda Canada Inc; holds a research grant funded by Abbott Laboratories, Amgen Inc, Bristol-Myers Squibb Canada, Janssen Global Services LLC, Hoffman La-Roche Inc, Pfizer Inc, and UCB Canada Inc. The remaining authors have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors provided financial and infrastructural support but played no role in the development of the research and manuscript.

Other contributions: The opinions, results, and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by the Institute for Clinical Evaluative Sciences or the Ontario Ministry of Health and Long-Term Care is intended or should be inferred.

Additional information: The e-Appendixes can be found in the Supplemental Materials section of the online article.

GERD

gastroesophageal reflux disease

HMO

health maintenance organization

HR

hazard ratio

NTM

nontuberculous mycobacteria

OHIP

Ontario Health Insurance Plan

RA

rheumatoid arthritis

TNF

tumor necrosis factor

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van Ingen J, Hoefsloot W, Dekhuijzen PN, Boeree MJ, van Soolingen D. The changing pattern of clinicalMycobacterium aviumisolation in the Netherlands. Int J Tuberc Lung Dis. 2010;14(9):1176-1180. [PubMed]
 
Dixon WG, Hyrich KL, Watson KD, et al; BSRBR Control Centre Consortium; BSR Biologics Register. Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR). Ann Rheum Dis. 2010;69(3):522-528. [CrossRef] [PubMed]
 
Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med. 2001;345(15):1098-1104. [CrossRef] [PubMed]
 
Brassard P, Kezouh A, Suissa S. Antirheumatic drugs and the risk of tuberculosis. Clin Infect Dis. 2006;43(6):717-722. [CrossRef] [PubMed]
 
Wallis RS, Broder M, Wong J, Beenhouwer D. Granulomatous infections due to tumor necrosis factor blockade: correction. Clin Infect Dis. 2004;39(8):1254-1255. [CrossRef] [PubMed]
 
Tubach F, Salmon D, Ravaud P, et al; Research Axed on Tolerance of Biotherapies Group. Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: the three-year prospective French Research Axed on Tolerance of Biotherapies registry. Arthritis Rheum. 2009;60(7):1884-1894. [CrossRef] [PubMed]
 
Gómez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD; BIOBADASER Group. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum. 2003;48(8):2122-2127. [CrossRef] [PubMed]
 
Raval A, Akhavan-Toyserkani G, Brinker A, Avigan M. Brief communication: characteristics of spontaneous cases of tuberculosis associated with infliximab. Ann Intern Med. 2007;147(10):699-702. [CrossRef] [PubMed]
 
Koetz K, Bryl E, Spickschen K, O’Fallon WM, Goronzy JJ, Weyand CM. T cell homeostasis in patients with rheumatoid arthritis. Proc Natl Acad Sci U S A. 2000;97(16):9203-9208. [CrossRef] [PubMed]
 
Au K, Reed G, Curtis JR, et al; CORRONA Investigators. High disease activity is associated with an increased risk of infection in patients with rheumatoid arthritis. Ann Rheum Dis. 2011;70(5):785-791. [CrossRef] [PubMed]
 
Popa C, Netea MG, Barrera P, et al. Cytokine production of stimulated whole blood cultures in rheumatoid arthritis patients receiving short-term infliximab therapy. Cytokine. 2005;30(2):72-77. [CrossRef] [PubMed]
 
Chan ED, Iseman MD. Slender, older women appear to be more susceptible to nontuberculous mycobacterial lung disease. Gend Med. 2010;7(1):5-18. [CrossRef] [PubMed]
 
Raso GM, Pacilio M, Esposito E, Coppola A, Di Carlo R, Meli R. Leptin potentiates IFN-gamma-induced expression of nitric oxide synthase and cyclo-oxygenase-2 in murine macrophage J774A.1. Br J Pharmacol. 2002;137(6):799-804. [CrossRef] [PubMed]
 
Kartalija M, Ovrutsky AR, Bryan CL, et al. Patients with nontuberculous mycobacterial lung disease exhibit unique body and immune phenotypes. Am J Respir Crit Care Med. 2013;187(2):197-205. [CrossRef] [PubMed]
 
Maurya V, Vijayan VK, Shah A. Smoking and tuberculosis: an association overlooked. Int J Tuberc Lung Dis. 2002;6(11):942-951. [PubMed]
 
Long R, Ellis E., eds. Canadian Tuberculosis Standards.6th ed. Ottawa, Canada: Canadian Lung Association and Health Canada; 2007.
 
Winthrop KL, Baxter R, Liu L, et al. The reliability of diagnostic coding and laboratory data to identify tuberculosis and nontuberculous mycobacterial disease among rheumatoid arthritis patients using anti-tumor necrosis factor therapy. Pharmacoepidemiol Drug Saf. 2011;20(3):229-235. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1  Key study definitions. ICD = International Classification of Diseases; M. = Mycobacterium.Grahic Jump Location
Figure Jump LinkFigure 2  Distribution of NTM species causing disease in RA and non-RA groups. A, RA group, pulmonary NTM; B, non-RA group, pulmonary NTM; C, RA group, nonpulmonary NTM; D, non-RA group, nonpulmonary NTM.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1  ] General Characteristics of Ontarians With and Without RAa

Data given as No. (%) unless otherwise indicated. GERD = gastroesophageal reflux disease; RA = rheumatoid arthritis.

a 

Ontarians aged ≥ 15 y as of 1/1/2001. People in the non-RA group never fulfilled RA criteria during the observation period, while people in the RA group fulfilled RA criteria at some time during the observation period.

Table Graphic Jump Location
TABLE 2  ] Mycobacterial Syndromes: Number of Cases, Incidence (per 100,000 Person-Y), and HRsa

HR = hazard ratio; NTM = nontuberculous mycobacteria. See Table 1 legend for expansion of other abbreviations.

a 

HR for mycobacterial syndrome in Ontarians with RA vs those without RA.

b 

Fully adjusted HR adjusted for age, sex, income, rurality, and comorbidities for TB: HIV, diabetes, and chronic kidney disease; and for NTM: HIV, COPD, asthma, and GERD.

c 

NTM disease: Pulmonary: isolation of the same NTM species from two or more sputum samples, or one or more bronchoscopy samples, excluding Mycobacterium gordonae; nonpulmonary: any positive culture from a normally sterile body site, excluding M gordonae (pleural isolates classified as nonpulmonary).

Table Graphic Jump Location
TABLE 3  ] Characteristics of TB and NTM Disease Cases Compared With Noncases Among People With RA

Data given as No. (%) unless otherwise indicated. According to privacy regulations, values representing fewer than six people are reported as ≤ 5. N/A = not applicable. See Table 1 and 2 legends for expansion of abbreviations.

a 

P value for comparison between TB cases and uninfected people.

b 

P value for comparison between NTM disease cases and uninfected people.

c 

Rural index for Ontario group is a measure of rurality designed for Ontario.24

d 

Fully adjusted HR adjusted for age, sex, income, rurality, presence of extraarticular RA, and comorbidities for TB: HIV, diabetes, and chronic kidney disease; and for NTM: HIV, COPD, asthma, and GERD.

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Askling J, Fored CM, Brandt L, et al. Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden. Arthritis Rheum. 2005;52(7):1986-1992. [CrossRef] [PubMed]
 
Winthrop KL, Baxter R, Liu L, et al. Mycobacterial diseases and antitumour necrosis factor therapy in USA. Ann Rheum Dis. 2013;72(1):37-42. [CrossRef] [PubMed]
 
Wolfe F, Michaud K, Anderson J, Urbansky K. Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy. Arthritis Rheum. 2004;50(2):372-379. [CrossRef] [PubMed]
 
Adjemian J, Olivier KN, Seitz AE, Holland SM, Prevots DR. Prevalence of nontuberculous mycobacterial lung disease in U.S. Medicare beneficiaries. Am J Respir Crit Care Med. 2012;185(8):881-886. [CrossRef] [PubMed]
 
Crowson CS, Matteson EL, Myasoedova E, et al. The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum. 2011;63(3):633-639. [CrossRef] [PubMed]
 
Tanoue LT. Pulmonary manifestations of rheumatoid arthritis. Clin Chest Med. 1998;19(4):667-685. [CrossRef] [PubMed]
 
Park S-W, Song JW, Shim TS, et al. Mycobacterial pulmonary infections in patients with idiopathic pulmonary fibrosis. J Korean Med Sci. 2012;27(8):896-900. [CrossRef] [PubMed]
 
van Ingen J, Hoefsloot W, Dekhuijzen PN, Boeree MJ, van Soolingen D. The changing pattern of clinicalMycobacterium aviumisolation in the Netherlands. Int J Tuberc Lung Dis. 2010;14(9):1176-1180. [PubMed]
 
Dixon WG, Hyrich KL, Watson KD, et al; BSRBR Control Centre Consortium; BSR Biologics Register. Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR). Ann Rheum Dis. 2010;69(3):522-528. [CrossRef] [PubMed]
 
Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med. 2001;345(15):1098-1104. [CrossRef] [PubMed]
 
Brassard P, Kezouh A, Suissa S. Antirheumatic drugs and the risk of tuberculosis. Clin Infect Dis. 2006;43(6):717-722. [CrossRef] [PubMed]
 
Wallis RS, Broder M, Wong J, Beenhouwer D. Granulomatous infections due to tumor necrosis factor blockade: correction. Clin Infect Dis. 2004;39(8):1254-1255. [CrossRef] [PubMed]
 
Tubach F, Salmon D, Ravaud P, et al; Research Axed on Tolerance of Biotherapies Group. Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: the three-year prospective French Research Axed on Tolerance of Biotherapies registry. Arthritis Rheum. 2009;60(7):1884-1894. [CrossRef] [PubMed]
 
Gómez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD; BIOBADASER Group. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum. 2003;48(8):2122-2127. [CrossRef] [PubMed]
 
Raval A, Akhavan-Toyserkani G, Brinker A, Avigan M. Brief communication: characteristics of spontaneous cases of tuberculosis associated with infliximab. Ann Intern Med. 2007;147(10):699-702. [CrossRef] [PubMed]
 
Koetz K, Bryl E, Spickschen K, O’Fallon WM, Goronzy JJ, Weyand CM. T cell homeostasis in patients with rheumatoid arthritis. Proc Natl Acad Sci U S A. 2000;97(16):9203-9208. [CrossRef] [PubMed]
 
Au K, Reed G, Curtis JR, et al; CORRONA Investigators. High disease activity is associated with an increased risk of infection in patients with rheumatoid arthritis. Ann Rheum Dis. 2011;70(5):785-791. [CrossRef] [PubMed]
 
Popa C, Netea MG, Barrera P, et al. Cytokine production of stimulated whole blood cultures in rheumatoid arthritis patients receiving short-term infliximab therapy. Cytokine. 2005;30(2):72-77. [CrossRef] [PubMed]
 
Chan ED, Iseman MD. Slender, older women appear to be more susceptible to nontuberculous mycobacterial lung disease. Gend Med. 2010;7(1):5-18. [CrossRef] [PubMed]
 
Raso GM, Pacilio M, Esposito E, Coppola A, Di Carlo R, Meli R. Leptin potentiates IFN-gamma-induced expression of nitric oxide synthase and cyclo-oxygenase-2 in murine macrophage J774A.1. Br J Pharmacol. 2002;137(6):799-804. [CrossRef] [PubMed]
 
Kartalija M, Ovrutsky AR, Bryan CL, et al. Patients with nontuberculous mycobacterial lung disease exhibit unique body and immune phenotypes. Am J Respir Crit Care Med. 2013;187(2):197-205. [CrossRef] [PubMed]
 
Maurya V, Vijayan VK, Shah A. Smoking and tuberculosis: an association overlooked. Int J Tuberc Lung Dis. 2002;6(11):942-951. [PubMed]
 
Long R, Ellis E., eds. Canadian Tuberculosis Standards.6th ed. Ottawa, Canada: Canadian Lung Association and Health Canada; 2007.
 
Winthrop KL, Baxter R, Liu L, et al. The reliability of diagnostic coding and laboratory data to identify tuberculosis and nontuberculous mycobacterial disease among rheumatoid arthritis patients using anti-tumor necrosis factor therapy. Pharmacoepidemiol Drug Saf. 2011;20(3):229-235. [CrossRef] [PubMed]
 
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